The objective this proposal is the delineation of novel pathogenic mechanisms underlying adverse pregnancy outcome associated with thrombophilia. Our work in the context of the parent proposal to study the function of the blood clotting regulator thrombomodulin (TM) has shown that the loss of TM function causes intrauterine fetal loss. We found that the developmental failure of TM-null mice is secondary to a defect in fetal trophoblast cells of the placenta. Contrary to the current concept of the pathogenic mechanism underlying the association of thrombophilia and adverse pregnancy outcome, the intrauterine death of TM-deficient embryos is not caused by thrombosis of placental blood vessels, but rather is due to the death of fetal trophoblast cells caused by fibrin degradation products, and a concomitant arrest of placental growth that is likely caused by inadvertent engagement of protease activated receptors (PAR's) for coagulation factors. Here, we wish to delineate the molecular mechanism underlying the fatal defects in fetal placental trophoblast of TM-deficient embryos and test the hypothesis that thrombophilia of the mother causes fetal loss through similar mechanism as those delineated in TM-deficient mice. To this end, we propose to (1) characterize the ligand, the receptor, and the intracellular apoptotic pathways mediating cell death induced by fibrin degradation products, (2) delineate the role of receptors for coagulation factors in the development and function of the placenta, and (3) establish a mouse model of fetal loss caused by thrombophilia of the mother that will enable investigations into the underlying pathogenesis. Results from these specific aims should provide potentially novel insights into the structural and functional basis of a previously unknown pathway regulating cell survival of placental trophoblast cells, test the working hypothesis that protease receptor engagement by coagulation factors regulates placental growth, and address the pathogenic mechanism underlying fetal loss experienced by mothers with underlying thrombophilic states, such as that caused by the factor V Leiden mutation.